Many cellular functions rely critically upon the proper physical organization of the cellular environment, including mechanical factors of force and spatial organization. We propose to use and develop nanotools to systematically explore the effects of physical cues, including force production and sensing, on the phenotypic behavior of cells and tissue constructs. The unifying theme that brings our team together is our joint interest in understanding the impact of physical factors, including mechanical force on cell function from various different perspectives, from the physical sciences, (nano)engineering to biomedicine. Major pioneering contributions to this newly emerging field have already been made by our team members in the past and they have all developed quantitative assays of cell functions. However, they have not joined in a concerted effort where expertise, tools and ideas were broadly shared to accelerate the progress. Our goats are to apply complementary sets of nanotools towards learning how biological systems respond to physical cues, and to develop new technologies from the insights derived. Our team includes mathematicians, computer modelers, physical and biological scientists and engineers and most have already collaborated in the past. We will delineate engineering design principles of biological nanosystems by integrating insights derived from bottom-up self assembled model systems (a reductionist's perspective) with observations made in biological systems under in-vivo conditions. In this context, we will focus on developing radically new ways to improve tissue repair, to develop new paradigms for tissue engineering, to control tissue shape and immune function, to advance our knowledge regarding pathways of bacterial adhesion and infection, and to engineer diagnostic devices or treatments. We have many outside collaborations and plan to spread the technology developed through workshops and other educational activities. There are also many obvious applications for the tools and technologies in screening and diagnosis as well as in designing new therapies.